EP0922111B1 - Induzierung von t zell toleranz unter verwendung eines löslichen moleküls, dass gleichzeitig zwei kostimulierungswege blockieren kann - Google Patents

Induzierung von t zell toleranz unter verwendung eines löslichen moleküls, dass gleichzeitig zwei kostimulierungswege blockieren kann Download PDF

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Publication number
EP0922111B1
EP0922111B1 EP19970930902 EP97930902A EP0922111B1 EP 0922111 B1 EP0922111 B1 EP 0922111B1 EP 19970930902 EP19970930902 EP 19970930902 EP 97930902 A EP97930902 A EP 97930902A EP 0922111 B1 EP0922111 B1 EP 0922111B1
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binding
antibody
antigen
human
molecule
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Expired - Lifetime
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EP19970930902
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French (fr)
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EP0922111A1 (de
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Mark De Boer
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Pangenetics BV
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Tanox Pharma BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70521—CD28, CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/626—Diabody or triabody
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/026—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a baculovirus

Definitions

  • CD40 belongs to the TNF receptor family of type I transmembrane proteins.
  • the members of this gene family which include: the two receptors for TNF; the low-affinity nerve growth factor receptor; the T cell activation antigen CD27; CD30 and; CD95, are characterized by sequence homology in their cysteine-rich extracellular domains (Armitage et al., Current Opinion in Immunology 6:407 (1994)).
  • T cell mediated diseases such as transplant rejection, multiple sclerosis, psoriasis, rheumatoid arthritis and systemic lupus erythematosus
  • the protective group has between 1 and 8 carbons, more preferably it is methyl.
  • n is a positive integer, preferably between 1 and 1,000, more preferably between 2 and 500.
  • the PEG has a preferred average molecular weight between 1000 and 40,000, more preferably between 2000 and 20,000, most preferably between 3,000 and 12,000.
  • PEG has at least one hydroxy group, more preferably it is a terminal hydroxy group. It is this hydroxy group which is preferably activated to react with a free amino group on the inhibitor. Water soluble polyoxyethylated polyols are also useful in the present invention.
  • compositions of this invention are used to prevent allograft rejection, to prevent xenograft rejection, or to treat autoimmune diseases.
  • the preferred route of administration is parentally.
  • the compositions of this invention will be formulated in a unit dosage injectable form such as a solution, suspension or emulsion, in association with a pharmaceutically acceptable parental vehicle.
  • a pharmaceutically acceptable parental vehicle are inherently nontoxic and nontherapeutic. Examples of such vehicles are saline, Ringer's solution, dextrose solution, and Hanks' solution. Nonaqueous vehicles such as fixed oils and ethyl oleate may also be used.
  • a preferred vehicle is 5% dextrose in saline.
  • the vehicle may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, including buffers and preservatives.
  • Cells (0.1-0.2 x 10 6 /sample) were incubated for 20 min at 4oC with the specific monoclonal antibody (0.1-1 mg/sampic). After washing with FACS buffer (PBS pH 7.4 1% BSA 0.1% NaN 3 ), the cells were incubated for another 20 min at 4oC with goat anti-mouse antibodies conjugated to fluorescein isothiocyanate (FITC) or phycoerythin (PE). The cells were washed with FACS buffer and finally suspended in FACS buffer containing 0.5% paraformaldehyde and analysed with a FACScan flow cytometer (Becton Dickinson). The specific binding of the monoclonal antibodies is expressed as the mean fluorescent intensity in arbitrary units.
  • FACS buffer PBS pH 7.4 1% BSA 0.1% NaN 3
  • FITC fluorescein isothiocyanate
  • PE phycoerythin
  • the conceptual therapeutic agent is a fusion protein combining the high affinity and specificity of CTLA4 for both CD80 and CD86 with an antagonistic anti-CD40 monoclonal antibody.
  • This fusion molecule is produced in stable, active form as a complete anti-CD40 monoclonal antibody to which the extracellular domain of human CTLA4 (CTLA4ED) is C-terminal linked by a flexible linker.
  • CTLA4ED human CTLA4
  • the construction of the anti-CD40 antibody attached by its Fc part to the extracellular domain of CTLA4 is done by the following PCR and cloning steps.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Cell Biology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Transplantation (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Rheumatology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
  • Optical Measuring Cells (AREA)

Claims (14)

  1. Ein lösliches Molekül, welches fähig ist, humanes CD40 Antigen zu binden, indem es wenigstens eine Antigenbindungsstelle eines Antikörpers gegen CD40 enthält und welches fähig ist, humanes CD86 Antigen zu binden, indem es wenigstens eine Antigenbindungsstelle eines Antikörpers gegen CD86 enthält, wobei sich die genannten Antigene auf der Oberfläche von humanen Lymphozyten oder Antigenpräsentierenden Zellen befinden.
  2. Ein Molekül gemäß Anspruch 1, welches ein Antikörper ist, der eine Antigenbindungsstelle eines Antikörpers gegen CD40 und eine Antigenbindungsstelle eines Antikörpers gegen CD86 enthält.
  3. Ein Molekül gemäß Anspruch 1, welches außerdem fähig ist, CD80 zu binden und welches die Antigenbindungsstelle eines Antikörpers enthält, der mit CD80 und CD86 kreuzreagiert.
  4. Ein Molekül gemäß Anspruch 1, welches ein bispezifischer Diabody ist, der fähig ist, humanes CD40 und humanes CD86 zu binden.
  5. Ein Molekül gemäß Anspruch 1, welches außerdem fähig ist, CD80 zu binden und welches die Antigenbindungsstelle eines Antikörpers gegen CD80 und die Antigenbindungsstelle eines Antikörpers gegen CD86 enthält.
  6. Ein Molekül gemäß Anspruch 1 oder 3, welches fähig ist, wenigstens CD86 mittels der extrazellulären Domäne von humanem CTLA-4 zu binden.
  7. Ein Molekül gemäß einem der Ansprüche 1-5, worin der Antikörper gegen CD86 der Antikörper Fun-1 ist.
  8. Ein Molekül gemäß einem der Ansprüche 1-7, worin der Antikörper gegen CD40 ein antagonistischer Antikörper gegen CD40 ist.
  9. Ein Molekül gemäß einem der Ansprüche 1-7, worin der Antikörper gegen CD40 ein nicht-stimulatorischer antagonistischer Antikörper gegen CD40 ist.
  10. Ein rekombinanter Vektor, welcher die für die bindenden Molekülfragmente gemäß einem der Ansprüche 1-9 kodierenden Nucleotidsequenzen, operativ verbunden mit Regulationssequenzen, die fähig sind, das Antikörpermolekül in einer Wirtszelle zu exprimieren, umfasst.
  11. Eine Wirtszelle, welche stabil mit dem Vektor gemäß Anspruch 10 transformiert ist.
  12. Ein Verfahren zur Herstellung eines rekombinanten Moleküls, welches fähig ist, humanes CD40 Antigen und wenigstens humanes CD86 Antigen zu binden und welches die Kultivierung der Wirtszelle gemäß Anspruch 11 und die Isolierung der bindenden Moleküle aus dem Kulturmedium umfasst.
  13. Eine pharmazeutische Zusammensetzung für die Induktion von T-Zelltoleranz, welche eine therapeutisch wirksame Menge des bindenden Moleküls gemäß einem der Ansprüche 1 bis 9 und einen pharmazeutisch annehmbaren Träger enthält.
  14. Verwendung eines bindenden Moleküls gemäß einem der Ansprüche 1-9 zur Herstellung einer pharmazeutischen Zusammensetzung für die Behandlung von T-Zell vermittelten Immunantworten, für die Prävention der Allotransplantat- oder Xenotransplantat-Abstoßung, für die Induktion von T-Zelltoleranz, für die Induktion von Allotransplantat- oder Xenotransplantat-Toleranz, für die Prävention oder Behandlung von Autoimmunkrankheiten wie z.B. rheumatoide Arthritis, multiple Sklerose und Psoriasis, oder für die Behandlung von T-Zell vermittelten Immunantworten gegenüber Gentherapievektoren oder -vehikeln oder gegenüber therapeutischen Molekülen.
EP19970930902 1996-07-23 1997-07-23 Induzierung von t zell toleranz unter verwendung eines löslichen moleküls, dass gleichzeitig zwei kostimulierungswege blockieren kann Expired - Lifetime EP0922111B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US2207096P 1996-07-23 1996-07-23
US22070P 1996-07-23
PCT/NL1997/000438 WO1998003670A1 (en) 1996-07-23 1997-07-23 Induction of t cell tolerance using a soluble molecule that can simultaneously block two costimulatory pathways

Publications (2)

Publication Number Publication Date
EP0922111A1 EP0922111A1 (de) 1999-06-16
EP0922111B1 true EP0922111B1 (de) 2004-12-01

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EP19970930902 Expired - Lifetime EP0922111B1 (de) 1996-07-23 1997-07-23 Induzierung von t zell toleranz unter verwendung eines löslichen moleküls, dass gleichzeitig zwei kostimulierungswege blockieren kann

Country Status (8)

Country Link
US (1) US20020150559A1 (de)
EP (1) EP0922111B1 (de)
JP (1) JP4219985B2 (de)
AT (1) ATE283925T1 (de)
CA (1) CA2260752A1 (de)
DE (1) DE69731836T2 (de)
HK (1) HK1017905A1 (de)
WO (1) WO1998003670A1 (de)

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AU8800598A (en) * 1997-06-20 1999-01-04 Innogenetics N.V. B7-binding molecules for treating immune diseases
WO1999039727A1 (en) * 1998-02-04 1999-08-12 The General Hospital Corporation Costimulatory blockade and mixed chimerism in allotransplantation
FR2789089A1 (fr) * 1999-02-02 2000-08-04 Pf Medicament Lymphocytes t humains effecteurs exprimant la molecule cd86 et possedant des proprietes immunodulatrices, costimulatrices et cytotoxiques, leurs procedes d'obtention et leurs applications
EP1839674A1 (de) * 1999-10-04 2007-10-03 Novartis Vaccines and Diagnostics, Inc. CD40-Antagonist zur Behandlung von Psoriase
DE60035057T2 (de) * 1999-10-04 2008-01-31 Novartis Vaccines and Diagnostics, Inc., Emeryville CD40 Antagonist zur Behandlung von Psoriasis
CA2406961A1 (en) * 2000-04-19 2002-02-14 Tanox, Inc. Cd40 antagonists for use in treating psoriasis and other inflammatory skin conditions
US20030059888A1 (en) * 2001-08-22 2003-03-27 Shengfeng Li Compositions and methods for generating antigen-binding units
US20070148162A1 (en) * 2003-02-27 2007-06-28 Ranjit Bhardwaj Molecule which binds cd80 and cd86
US20070009517A1 (en) * 2003-08-25 2007-01-11 Mark De Boer Method of inducing immune tolerance
EP1854810A1 (de) 2006-05-09 2007-11-14 PanGenetics B.V. De-immunisierter und antagonister monoclonaler Antikörper gegen CD40, der aus der ch5D12 Antikörper abgeleitet ist
EP2195341B1 (de) * 2007-09-26 2017-03-22 UCB Biopharma SPRL Fusionsantikörper mit dualer spezifität
EA201100527A1 (ru) * 2008-09-26 2011-10-31 Юсб Фарма С.А. Биологические продукты
EP2344540B1 (de) * 2008-10-02 2017-11-29 Aptevo Research and Development LLC Multitarget-bindungsproteine mit cd86-antagonist
US20110217302A1 (en) * 2008-10-10 2011-09-08 Emergent Product Development Seattle, Llc TCR Complex Immunotherapeutics
AU2013249267A1 (en) 2012-04-20 2014-10-23 Aptevo Research And Development Llc CD3 binding polypeptides
EP2948475A2 (de) * 2013-01-23 2015-12-02 AbbVie Inc. Verfahren und zusammensetzungen zur modulierung einer immunantwort
EP2883883A1 (de) 2013-12-16 2015-06-17 Cardio3 Biosciences S.A. Therapeutische Ziele und Mittel zur Behandlung von ischämiebedingten Reperfusionsschäden
EP2930188A1 (de) * 2014-04-13 2015-10-14 Affimed Therapeutics AG Trifunktionelles Antigen-bindendes Molekül
TWI742423B (zh) 2014-05-29 2021-10-11 美商宏觀基因股份有限公司 特異性結合多種癌症抗原的三特異性結合分子和其使用方法
EP3352760A4 (de) 2015-09-21 2019-03-06 Aptevo Research and Development LLC Cd3-bindende polypeptide
RU2731202C2 (ru) 2015-10-08 2020-08-31 Макродженикс, Инк. Комбинированная терапия для лечения рака
CN108264561B (zh) * 2016-12-30 2021-09-10 惠和生物技术(上海)有限公司 一种结合cd19、cd3和t细胞负共刺激分子的三功能分子及其应用

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Also Published As

Publication number Publication date
US20020150559A1 (en) 2002-10-17
WO1998003670A1 (en) 1998-01-29
EP0922111A1 (de) 1999-06-16
JP2000515374A (ja) 2000-11-21
DE69731836T2 (de) 2005-12-01
DE69731836D1 (de) 2005-01-05
CA2260752A1 (en) 1998-01-29
HK1017905A1 (en) 1999-12-03
JP4219985B2 (ja) 2009-02-04
ATE283925T1 (de) 2004-12-15

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